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Bilirubin Metabolism:

Introduction:

I ntroduction Bilirubin is the orange-yellow pigment derived from senescent red blood cells. It is a toxic waste product in the body. It is extracted and biotransformed mainly in the liver, and excreted in bile and urine. It is a bile pigment Elevations in serum and urine bilirubin levels are normally associated with Jaundice.

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Erythrocytes become “old” as they lose their flexibility and become pikilocytes (spherical), increasingly rigid and fragile. Once the cell become fragile, they easily destruct during passage through tight circulation spots, especially in spleen, where the intra-capillary space is about 3 micron as compared to 8 micron of cell size RBCs useful life span is 100 to 120 days,After which they become trapped and fragment in smaller circulatory channels, particularly in those of the spleen. For this reason, the spleen is sometimes called the “red blood cell graveyard.” Dying erythrocytes are engulfed and destroyed by macrophages.

Formation of Bilirubin:

Formation of Bilirubin Primary site of synthesis:- SPLEEN : The Graveyard of Red Blood Cells Secondary site of synthesis:- LIVER & BONE MARROW

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An average person produces about 4 mg/kg of bilirubin per day. The daily bilirubin production from all sources in man averages from 250 to 300 mg .

Extravascular Pathway for RBC Destruction:

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Within cells of the RE system, heme degraded to bilirubin in a two-step process . a. The porphyrin ring is opened and the iron atom is removed by the action of heme oxygenase to produce the green-colored intermediate biliverdin . b. Subsequent reduction converts biliverdin to bilirubin , which has a redorange color.

Pathophysiology:

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The globin is recycled or converted into amino acids , which in turn are recycled or catabolized as required. Heme is oxidized, with the heme porphyrin ring being opened by the endoplasmic reticulum enzyme, heme oxygenase . The oxidation occurs on a specific carbon producing equimolar amounts of the biliverdin , iron , and carbon monoxide (CO) . This is the only reaction in the body that is known to produce CO. Most of the CO is excreted through the lungs, with the result that the CO content of expired air is a direct measure of the activity of heme oxygenase in an individual.

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III IV I II Oxidation Heme Oxygenase In the first reaction, a bridging methylene group is cleaved by heme oxygenase to form Linear Biliverdin from Cyclic Heme molecule. Fe 2 + is released from the ring in this process.

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I II III IV Fe 2+ NADP H C O 2 O O 2 Heme Oxygenase O

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I II III IV Biliverdin

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NADP H H Bilirubin

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In the next reaction, a second bridging methylene (between rings III and IV) is reduced by biliverdin reductase, producing bilirubin . I I III III IV IV II II Reduction Biliverdin Reductase

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biliverdin causing a change in the color of the molecule from blue-green ( biliverdin ) to yellow-red ( bilirubin ). The latter catabolic changes in the structure of tetrapyrroles are responsible for the progressive changes in color of a hematoma, or bruise, in which the damaged tissue changes its color from an initial dark blue to a red-yellow and finally to a yellow color before all the pigment is transported out of the affected tissue. Peripherally arising bilirubin is transported to the liver in association with albumin, where the remaining catabolic reactions take place.

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Bilirubin is not very water-soluble, so most of it is carried to the liver bound to albumin.

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In cells of the liver, bilirubin undergoes modification to increase its water solubility so that it can be excreted more easily . Bilirubin is conjugated to two molecules of glucuronic acid, creating bilirubin diglucuronide . b. Bilirubin diglucuronide is transported out of the hepatocytes into the bile canaliculi and is thus excreted in bile.

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In Endoplasmic Reticulum In the microsomes of the endoplasmic reticulum, unconjugated bilirubin is converted to water soluble mono- or di - conjugates by sequential covalent coupling with glucuronic acid.

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Bilirubin is conjugated in a two step process to form bilirubin mono- & di- glucuronide

Conjugation with Glucoronates:

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Excretion of Bilirubin

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In the Intestine In the small intestine, conjugated bilirubins are poorly reabsorbed, but are partly hydrolyzed back to unconjugated bilirubin by catalytic action of bacterial ß-glucuronidases. In the distal ileum and colon, anaerobic flora mediate further catabolism of bile pigments: hydrolysis of conjugated bilirubin to unconjugated bilirubin by bacterial β -glucuronidases; multistep hydrogenation (reduction) of unconjugated bilirubin to form colorless urobilinogens; and oxidation of unconjugated bilirubin to brown colored mesobilifuscins .

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Urobilinogens is a collective term for a group of 3 tetrapyrroles; Stercobilinogen (6H) Mesobilinogen (8H)&, Urobilinogen (12H) Upto 20 % of urobilinogen produced daily is reabsorbed from the intestine & enters the entero-hepatic circulation. Urobilinogen Structure

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Most of the reabsorbed urobilinogen is taken up by the liver & is re-excreted in the bile. A small fraction (2 % - 5 %) enters the general circulation & appears in the urine. In the lower intestinal tract, the 3 urobilinogens spontaneously oxidize to produce the corresponding bile pigments; Stercobilin Mesobilin & Urobilin; which are orange-brown in color and are the major pigments of stool.

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JAUNDICE

Clinical Significance:

Clinical Significance Hyperbilirubinemia & Types of Jaundice Hyperbilirubinemia : Increased plasma concentrations of bilirubin (> 3 mg/dl) occurs when there is an imbalance between its production and excretion. Recognized clinically as jaundice. Also known as icterus, a yellow discoloration of the skin, sclerae and mucous membrane.

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Hepatic jaundice Impaired uptake, conjugation, or secretion of bilirubin Reflects a generalized liver ( hepatocyte ) dysfunction In this case, hyperbilirubinemia is usually accompanied by other abnormalities in biochemical markers of liver function

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Hemolytic jaundice arises as a consequence of excessive destruction of RBCs. – This overloads the capacity of the RE system to metabolize heme . – Failure to conjugate bilirubin to glucuronic acid causes accumulation of bilirubin in the unconjugated form in the blood.

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Posthepatic (Obstructive) jaundice Caused by an obstruction of the biliary tree. Plasma bilirubin is conjugated, and other biliary metabolites, such as bile acids accumulate in the plasma. Characterized by pale colored stools (absence of fecal bilirubin or urobilin ), and dark urine (increased conjugated bilirubin ). In a complete obstruction, urobilin is absent from the urine.

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• Obstructive jaundice, as the name implies, is caused by blockage of the bile duct by a gallstone or a tumor (usually of the head of the pancreas). – This prevents passage of bile into the intestine and consequently conjugated bilirubin builds up in the blood. – Patients with this condition suffer severe abdominal pain associated with the obstruction (if due to gallstone ) and their feces are gray in color due to lack of stercobilin .

Neonatal Jaundice :

Neonatal Jaundice Common, particularly in premature infants. Transient (resolves in the first 10 days). Due to immaturity of the enzymes involved in bilirubin conjugation. High levels of unconjugated bilirubin are toxic to the newborn – due to its hydrophobicity it can cross the blood-brain barrier and cause a type of mental retardation known as kernicterus If bilirubin levels are judged to be too high, then phototherapy with UV light is used to convert it to a water soluble, non-toxic form.

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If necessary, exchange blood transfusion is used to remove excess bilirubin Phenobarbital is oftentimes administered to Mom prior to an induced labor of a premature infant – crosses the placenta and induces the synthesis of UDP glucuronyl transferase Jaundice within the first 24 hrs of life or which takes longer then 10 days to resolve is usually pathological and needs to be further investigated

Phototherapy:

Phototherapy Phototherapy is usually not needed unless the bilirubin levels rise very quickly or go above 16-20 mg/dl in healthy, full term babies. During phototherapy, the treatment of choice for jaundice, babies are placed under blue lights that convert the bilirubin into compounds that can be eliminated from the body.

Bilirubin Toxicity - Kernicterus:

Bilirubin Toxicity - Kernicterus Kernicterus or brain encephalopathy refers to the yellow staining of the deep nuclei (i.e., the kernel) of the brain namely, the basal ganglia. It is a form of permanent brain damage caused by excessive jaundice. The concentration of bilirubin in serum is so high that it can move out of the blood into brain tissue by crossing the fetal blood-brain barrier. This condition develops in newborns with prolonged jaundice due to: Polycythemia Rh incompatibility between mother & fetus

Crigler-Najjar Syndrome (Type I):

Crigler-Najjar Syndrome (Type I) Crigler-Najjar Syndrome (Type I) is a rare genetic disorder caused by complete absence of UDP-glucuronyltransferase and manifested by very high levels of unconjugated bilirubin. It is inherited as an autosomal recessive trait. Most patients die of severe brain damage caused by kernicterus within the first year of life. Early liver transplantation is the only effective therapy.

Crigler-Najjar Syndrome (Type II):

Crigler-Najjar Syndrome (Type II) This is a rare autosomal dominant disorder. It is characterized by partial deficiency of UDP-glucuronyltransferase. Unconjugated bilirubin is usually 5 – 20 mg/dl. Unlike Crigler-Najjar Type I, Type II responds dramatically to Phenobarbital & a normal life can be expected.

Gilbert’s Syndrome:

Gilbert’s Syndrome Gilbert’s syndrome is also called as familial non-hemolytic non-obstructive jaundice. mild unconjugated Hyperbilirubinemia . It affects 3% – 5% of the population. It is often misdiagnosed as chronic Hepatitis. The concentration of Bilirubin in serum fluctuates between 1.5 & 3 mg/dl. In this condition the activity of hepatic glucuronyltransferase is low as a result of mutation in the bilirubin -UDP- glucuronyltransferase gene(UGT1A1).

Dubin-Johnson Syndrome:

Dubin-Johnson Syndrome It is a benign, autosomal recessive condition characterized by jaundice with predominantly elevated conjugated bilirubin and a minor elevation of unconjugated bilirubin. Excretion of various conjugated anions and bilirubin into bile is impaired, reflecting the underlying defect in canalicular excretion. The Liver has a characteristic greenish black appearance and liver biopsy reveals a dark brown melanin-like pigment in hepatocytes and kupffer cells.

Rotor’s Syndrome:

Rotor’s Syndrome It is another form of conjugated hyperbilirubinemia. It is similar to dubin-johnson syndrome but without pigmentation in liver.